LSD1 is a targetable vulnerability in gastric cancer harboring TP53 frameshift mutations

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• TP53 mutations are associated with aggressive gastric cancer (GC) and chemoresistance.
• Frameshift mutations represent the second most common TP53 mutation type in GC, yet their impact and targeted therapies remain unclear.
• Histone methylation plays a role in TP53-mutated cancers, with inhibitors showing therapeutic potential.

Purpose of the Study:

• To investigate the consequences of TP53 frameshift mutations in gastric cancer.
• To identify targeted therapies for GC patients with specific TP53 mutations.
• To explore the role of histone methylation in TP53-mutated GC.

Main Methods:

• Screening of histone demethylase inhibitors against GC cell lines with various TP53 mutations.
• In vitro and in vivo evaluation of GSK690 efficacy in TP53 Frameshift ^NLS GC models.
• Dual-luciferase assays and ChIP-qPCR to elucidate the molecular mechanisms involving p53, LSD1, and CCNA2.

Main Results:

• GSK690, a lysine-specific demethylase 1 (LSD1) inhibitor, selectively inhibited GC cells with TP53 frameshift mutations lacking nuclear localization sequence (TP53 Frameshift ^NLS), comprising 89% of such mutations in GC.
• GSK690 induced G1/S cell cycle arrest via the LSD1-CCNA2 axis, demonstrating specific inhibition both in vitro and in vivo.
• Loss of p53 transcriptional repression activity was found to drive LSD1 upregulation in TP53 Frameshift ^NLS cancer cells.

Conclusions:

• Nuclear localization deficiency of p53 leads to increased LSD1 expression in TP53 Frameshift ^NLS GCs.
• GSK690 effectively inhibits cell cycle progression and tumor growth by targeting the aberrant LSD1-CCNA2 signaling pathway in this GC subtype.
• This study provides a precise therapeutic strategy for gastric cancer patients harboring TP53 Frameshift ^NLS mutations.